Carboxyl containing compounds, including most non-steroidal antiinflammatory drugs (NSAIDs), are difficult to formulate into stable, preserved, comfortable, ophthalmic compositions. Acidic drugs with carboxyl groups are inherently irritating to the eye. In addition, the drugs tend to form insoluble complexes with quaternary ammonium preservatives, such as benzalkonium chloride (BAC). Many NSAIDs have been formulated with other than desirable preservatives (e.g. sorbic acid, thimerosol) because the compounds complex with desired preservatives, such as, quaternary ammonium compounds, particularly BAC. In addition, it has proved difficult to formulate carboxyl containing compounds that are comfortable when applied topically to the eye.
There are ophthalmic products containing acidic drugs. Commonly, these drugs are NSAIDs containing a carboxyl group. Examples of these products are suprofen (Profenal.RTM., Alcon Laboratories, Inc. which is preserved with thimerosol); diclofenac sodium (Voltaren Ophthalmic.TM., Ciba Vision Ophthalmics which is preserved with sorbic acid); flurbiprofen sodium (Ocufen.RTM., Allergan Medical Optics which is preserved with thimerosol); and ketorolac tromethamine (Acular.RTM., Allergan, Inc. which is preserved with BAC and Octoxynol 40).
U.S. Pat. No. 5,110,493 discloses aqueous, ophthalmic, non-steroidal anti-inflammatory formulations which include a preservative system formed of a quaternary ammonium compound and a nonionic surfactant which is an ethoxylated alkyl phenol, such as Octoxynol 10 or 40.
WO 94/15597 discloses the use of lauralkonium chloride, a C.sub.12 homologue of BAC, which is compatible with acidic drug entities in ophthalmic formulations.
U.S. Pat. No. 4,960,799 discloses an ophthalmic formulation of a salt of ortho-(2,6-dichlorophenyl) aminophenylacetic acid, EDTA, a solubilizer, and a bacteriostat.
EP 0,621,036-A1 discloses ophthalmic formulations of particular arginine amides and either cyclodextrin or caffeine. The application discloses that the use of cyclodextrin or caffeine improves the arginine amide solubility in water and that the caffeine can stabilize the compound in water.
U.S. Pat. No. 4,559,343 discloses ophthalmic formulations containing NSAIDs and a xanthine derivative to reduce ocular discomfort.
The compositions of the present invention are stable, yet they contain an acidic drug and the desired preservative, BAC, or mixtures of at least two homologues of BAC. In addition, the compositions are comfortable upon topical instillation in the eye.